PT  - JOURNAL ARTICLE
AU  - Oikawa, Daisuke
AU  - Gi, Min
AU  - Kosako, Hidetaka
AU  - Shimizu, Kouhei
AU  - Takahashi, Hirotaka
AU  - Shiota, Masayuki
AU  - Hosomi, Shuhei
AU  - Komakura, Keidai
AU  - Wanibuchi, Hideki
AU  - Tsuruta, Daisuke
AU  - Sawasaki, Tatsuya
AU  - Tokunaga, Fuminori
TI  - OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways
AID  - 10.1101/2021.12.26.474226
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.26.474226
4099  - http://biorxiv.org/content/early/2021/12/27/2021.12.26.474226.short
4100  - http://biorxiv.org/content/early/2021/12/27/2021.12.26.474226.full
AB  - Deubiquitylating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolysing K63-linked ubiquitin chains from NF-κB signalling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. The N-terminal intrinsically disordered region of OTUD1, which contains an EGTE motif, is indispensable for KEAP1-binding and NF-κB suppression. OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1-/--mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.Competing Interest StatementThe authors have declared no competing interest.